We have tested these theories by transiently depleting central 5-HT by the dietary technique of acute tryptophan(Drug information on tryptophan) depletion (ATD) coupled with anxiety-specific challenges, and by neuroimaging subjects with anxiety disorders pre- and post-SSRI treatment.10,11 Using the first method, we have demonstrated that patients who have SSRI-remitted social anxiety disorder, panic disorder, or posttraumatic stress disorder experience a transient return of anxiety symptoms when central 5-HT is depleted. This supports the 5-HT deficit model.12 We have not elicited significant anxiety symptoms in subjects with SSRI-remitted generalized anxiety disorder, obsessive-compulsive disorder, or CBT-remitted panic disorder. Thus, according to this pharmacological dissection technique, it would appear that there is more to recovery than maintaining central 5-HT in these disorders.
Neuroimaging has demonstrated down-regulation of cerebral 5-HT1A receptors in patients with panic disorder and social anxiety disorder.11,13 A study by Nash and colleagues11 showed that the receptor down-regulation was localized to regions known to play an important role in anxiety states (ie, amygdala, orbitofrontal cortex, and temporal cortices), with some evidence of normalization of 5-HT1A binding with SSRI treatment.
Clearly, other neurotransmitter systems are also important in the treatment of anxiety disorders. Anxiolytics with norepinephrine(Drug information on norepinephrine) reuptake properties or g-aminobutyric acid–A (GABAA) agonism, for example, are in common use, and cross talk between neurotransmitter systems is well described. Recent interest in neuropeptides (which are virtually always co-localized in the CNS with at least 1 of the classic neurotransmitters) and neurotrophic factors adds additional complexity. While recognizing the broader context in which serotonergic agents operate, we focus our attention on more direct modification of 5-HT via SSRI medications.
Panic disorder and hypertension
Philosophical distinction between mind and body can be traced back to the ancient Greeks; however, it is René Descartes14 to whom we owe credit for the first systematic account of mind/body dualism. Discrimination between mental and physical phenomena characterized psychiatry and medicine until the end of the 20th century (some would suggest that it continues to this day). The rise of a voice for consumers, deliberate moves to destigmatize mental illness by a range of interest groups, and a trend away from traditional medical models of health care have prompted more integrated approaches.
The interface between psychiatry and cardiovascular medicine is a topic of immense current research interest, and although the past 15 years have seen scientific evidence catch up with the common wisdom linking depression to cardiovascular disease, anxiety and cardiovascular comorbidity has been little studied.2 In fact, there is considerable evidence that people with anxiety disorders have elevated cardiovascular mortality.15 When patients with panic attacks present to the emergency department fearing imminent cardiovascular collapse, their valid concerns often fall on deaf ears—panic disorder recognition rates as low as 2% have been reported in this setting!16,17
Hypertension is an independent risk factor for cardiovascular disease. It may be a cause or a consequence of endothelial dysfunction. An increase in blood pressure over the optimal 120/80 mm Hg increases the risk of cardiovascular events. Several authors have demonstrated an epidemiological association between cardiovascular disorders and anxiety disorders. Two large controlled studies have provided evidence for an association of hypertension with panic attacks and panic disorder, including one conducted by members of our group in Sheffield, England. This was a study of 891 patients in 3 groups—hypertensive patients in primary care, matched normotensive controls from the same primary care practice, and hypertensive patients attending a hospital clinic.
Davies and colleagues18 found that 37% of the hypertensive patients had experienced panic attacks compared with 21% of normotensive controls—a highly significant difference (P < .001). Panic disorder was significantly more common in hypertensive patients in primary care than in matched normotensive controls. Prospective studies have also reported on this association, although none of these studies had combined a robust method for diagnosing panic disorder and robust methods for diagnosing cardiovascular end points.
Why might an association between panic disorder and hypertension exist? A possibility is that patients with panic disorder have higher blood pressures because of a greater “white coat” (health-anxiety–related) hypertension response compared with patients without panic disorder. Davies and colleagues19 have also looked at this, finding that although a white coat effect exists, there was no difference in this effect in patients with panic disorder and in those without, making this explanation unlikely. The issue of whether normal-weight essential hypertension can be caused by chronic mental stress, such as panic disorder, is debated; however, Esler and colleagues20 have argued persuasively that in both conditions the increase in levels of plasma cortisol, (stress-induced) tissue nerve growth factor, subcortical norepinephrine turnover, and epinephrine(Drug information on epinephrine) cotransmission in sympathetic nerves support this assertion. It follows that the interplay of 5-HT with autonomic nervous system abnormalities in these patients warrants careful scrutiny.